The invention relates to a stable aqueous folinate solution.
Folinic acid is a metabolite of folic acid and is the active form into which folic acid is converted in the body. This conversion is inhibited by some cytostatics such as methotrexate. In order to overcome this problem, folinic acid has to be added. Folinic acid is further used in the case of folic acid deficiency, and it has a synergistic effect in combination with 5-fluorouracil. The customary form in which folinic acid is added is calcium folinate which is administered by infusion or injection. Calcium folinate is readily soluble but it does not keep at room temperature and therefore cannot be stored for prolonged periods at room temperature. At refrigerator temperatures, where the folinate does store well, a relatively concentrated solution is not stable; at the normal refrigerator temperature of approximately 4xc2x0 C., crystallization takes place at a concentration of as little as 15 mg/ml.
EP 0 401 895 provides folinate solutions with a relatively high concentration which are stable at refrigerator temperature. These solutions contain folinate ions, calcium ions and a complexing agent for calcium. The complexing agent and calcium form a complex. These solutions may be stable at refrigerator temperature in a concentration of as much as 50 mg/ml of folinate. The complexing agent used can be, for example, a sodium salt of ethylenediaminetetraacetic acid.
It has been found that a stable aqueous solution of folinic acid can be obtained simply by preparing an aqueous solution of sodium folinate. Even in a high concentration, up to about 400 mg of folinic acid per ml, it is stable in the refrigerator, i.e., does not crystallize. The aqueous solution of sodium folinate has a concentration of folinic acid in the range of about 15 to 400 mg/ml, preferably in the range of about 15 to 40 mg/ml or in the range of about 20 to 400 mg/ml, and more preferably in the range of about 25 to 400 mg/ml. The solution is stable at a pH range of 4.0 to 10.0, especially from 6.0 to 10.0, and preferably about 8.0 to 9.0.
Preferably, the solution contains a stabilizer, such as sodium citrate or sodium acetate. These salts further increase the stability of the solution. The present folinate solution also comprises an isotonizing agent such as sodium chloride.
It is also advantageous to incorporate a pharmaceutically acceptable buffer into the aqueous folinate solution according to the invention. Such a pharmaceutically acceptable buffer is preferably tris, a phosphate or a carbonate buffer, and is present in a concentration which is effective for obtaining the required pH.